The quest to improve survival of children with a high-risk brain tumor has led investigators to two drugs already used to treat adults with breast, pancreatic, lung, and other cancers.

Researchers demonstrated that the drugs pemetrexed and gemcitabine killed cells from mouse and human group 3 medulloblastoma tumors, growing in the laboratory. Medulloblastoma is diagnosed in about 400 children annually in the United States, making it the most common pediatric brain tumor. Of the four distinct medulloblastoma subtypes, patients with group 3 medulloblastoma have the worst prognosis.

Used together, pemetrexed and gemcitabine doubled life expectancy of mice with human group 3 medulloblastoma, compared to untreated mice. When pemetrexed and gemcitabine were combined with two chemotherapy drugs currently used to treat pediatric medulloblastoma, the mice lived even longer. The study, conducted at St. Jude Children's Research Hospital in Memphis, Tennessee, was published in Cancer Cell (2014; doi:10.1016/j.ccr.2014.02.009).

The drugs were identified by screening the St. Jude library of 7,389 compounds looking for ones that targeted group 3 mouse tumor cells rather than normal mouse brain cells, including all 830 FDA-approved drugs. Pemetrexed and gemcitabine emerged as the top candidates, based in part on their ability to kill group 3 medulloblastoma tumor cells at concentrations that researchers showed were safe and achievable in patients.

“Our focus was to identify drugs that we could move quickly from the laboratory to the clinic where new chemotherapy options are desperately needed for these high-risk medulloblastoma patients,” said the study's corresponding author Martine Roussel, PhD, of St. Jude. “As a basic scientist, it is exciting to be able to translate a laboratory discovery into drugs that are now being used in a clinical trial.”

Based on results from this and previous studies, pemetrexed and gemcitabine were included in a St. Jude-led multicenter clinical trial of children and adolescents with newly diagnosed medulloblastoma. The drugs are already approved for treatment of patients with advanced breast cancer as well as ovarian, pancreatic, and certain lung cancers. No safety concerns were identified in previous studies of pemetrexed and gemcitabine for treatment in children with other cancers.

Most group 3 medulloblastoma tumors feature excessive levels of the c-MYC protein, which helps to regulate cell growth. The protein is overexpressed in many cancers and is associated with a poor outcome. About 40% of patients with c-MYC overexpression and other characteristics of group 3 medulloblastoma become long-term survivors, compared to 80% of other medulloblastoma patients.

“The drugs identified in this study will hopefully close that survival gap and improve cure rates for children with group 3 medulloblastoma,” said co-author Amar Gajjar, MD, also of St. Jude.

For this study, researchers relied on mice with group 3 medulloblastoma grown from patient tumors. Researchers used the mice to show that pemetrexed and gemcitabine worked against human group 3 tumors and that the drugs could be used in combination with existing chemotherapy agents to boost treatment effectiveness without undue risk. Cisplatin and cyclophosphamide were the other drugs used in this study.